VIBRANT clinical data augmentation

The purpose of this document is to create

• a participants table with critical participant-invariant information (arm, site, etc.), including the population flags along with a

  • participants_variable_dictionary

• a visits_long table with the visit_code and study_day for each participant and each CRFs. This table is used to identify residual discrepancies between CRFs in visit_code and study_day (and harmonize them if needed).

• a visits table with one row per pid and visit_code and the following columns

  • study_day harmonized study_day across CRFs
  • visit_type: whether it is a clinic or home visit
  • visit_planned: whether the visit was planned or additional
  • visit_attended: whether the visit was attended or not. For home visits, this notes whether we have any CRF data for that visit
  • specimen_collection_swab (collected, not collected, unclear) [CRF35]
  • specimen_collection_softcup (collected, not collected, unclear) [CRF35]
  • specimen_collection_cytobrush (collected, not collected, unclear) [CRF35]
  • specimen_collection_home_swab (collected, not collected, unclear) [CRF47]

  along with a

  • visits_variable_dictionary

We will first create the participants table with pid, site, location, randomized and arm, then we will build the visits table because we need the correspondance between visit_code and study_day for some of the criteria to build the population flags (ITT, mITT and PP).

Load the crf data processed in the previous step 01a clinical CRF data cleaning.qmd

data_dir <- get_01_output_dir()

crf_clean_file <- data_dir |> fs::dir_ls() |> str_subset("01_crf_clean") |> sort(decreasing = TRUE) |> magrittr::extract(1)
load(crf_clean_file, verbose = TRUE)

Loading objects:
  crf_clean

crf_clean |> names()

 [1] "crf1"          "crf101"        "crf2"          "crf102"       
 [5] "crf3"          "crf4"          "crf5"          "crf6"         
 [9] "crf7"          "crf8"          "crf9"          "crf10"        
[13] "crf11"         "crf12"         "crf13"         "crf14"        
[17] "crf15"         "crf16"         "crf17"         "crf18"        
[21] "crf19"         "crf20"         "crf21"         "crf22"        
[25] "crf23"         "crf24"         "crf25"         "crf26"        
[29] "crf27"         "crf27_long"    "crf28"         "crf29"        
[33] "crf29_summary" "crf30"         "crf31"         "crf32"        
[37] "crf33"         "crf34"         "crf35"         "crf40"        
[41] "crf41"         "crf42"         "crf43"         "crf44"        
[45] "crf45"         "crf46"         "crf47"         "crf47_long"   

rm(crf_clean_file)

exposure_file <- data_dir |> fs::dir_ls() |> str_subset("01_exposures") |> sort(decreasing = TRUE) |> magrittr::extract(1)
load(exposure_file, verbose = TRUE)

Loading objects:
  exposures

rm(exposure_file)

participants table

The participants table will contain one row per pid for all pids identified throughout all CRFs and the following columns:

• pid: participant ID

• site (MGH or CAP)

• location: location of the participant (US or SA)

• randomized: whether the participant was randomized

• arm: the participant’s arm

  • one of NA if not randomized,
  • Blinded when still blinded,
  • Pl if randomized to the Placebo
  • LC106-7 if randomized to 7 days of LC106 after metronidazole
  • LC106-3 if randomized to 3 days of LC106 after metronidazole
  • LC106-o if randomized to 7 days of LC106 overlaping with metronidazole
  • LC115 if randomized to 7 days of LC115 after metronidazole

• ITT intention-to-treat population flag (TRUE or FALSE)

• mITT modified intention-to-treat population flag (TRUE or FALSE)

• PP per-protocol population flag (TRUE or FALSE)

All pids

participants <- 
  map(
    crf_clean, 
    function(x) x |> filter(!is.na(pid)) |> select(pid) |> distinct() |> mutate(pid = pid |> as.character())
  ) |> 
  bind_rows() |> 
  distinct()

Study site

participants <- 
  participants |> 
  mutate(
    site = 
      case_when(
        str_detect(pid, "^06810") | str_detect(pid, "^10") ~ "MGH",
        str_detect(pid, "^06820") | str_detect(pid, "^20")  ~ "CAP",
        TRUE ~ NA_character_
        ),
    location = ifelse(site == "MGH", "US", "SA")
  )

Randomization (randomized and arm)

Randomization data is available in CRF13. Randomized participants are participants with a treatment_code.

all(crf_clean$crf13$dfseq == 1000)
!any(is.na(crf_clean$crf13$treatment_code))
!any(duplicated(crf_clean$crf13$pid))

participants <- 
  participants |> 
  select(-any_of(c("randomized", "group4", "arm"))) |> 
  left_join(
    crf_clean$crf13 |> select(pid, group4) |> mutate(randomized = TRUE, pid = pid |> as.character()),
    by = join_by(pid)
  ) |> 
  mutate(
    randomized = randomized |> replace_na(FALSE)
  )

# For now, we do not know the arms yet, only whether participants were in the overlap arm or not.

participants <- 
  participants |> 
  mutate(
    arm = 
      case_when(
        group4 == "Yes" ~ "LC106-o",
        group4 == "No" ~ "Blinded",
        is.na(group4) ~ NA_character_
      ) |> 
      factor(
        levels = c("Pl", "LC106-7", "LC106-3", "LC106-o", "LC115", "Blinded")
        )
  ) |> 
  select(-group4)

participants |> 
  dplyr::count(site, randomized, arm) |> 
  gt(caption = "Number of randomized participants per site and per arm")

Number of randomized participants per site and per arm

site	randomized	arm	n
CAP	FALSE	NA	393
CAP	TRUE	LC-106-o	15
CAP	TRUE	Blinded	57
MGH	FALSE	NA	43
MGH	TRUE	LC-106-o	1
MGH	TRUE	Blinded	23

Visit tables (visits_long and visits)

visits_long

We build the visits_long table by concatenating the pid, visit_code, and study_day from all CRFs. It consequently has the following columns

• pid
• visit_code
• study_day
• crf_plate

visit_crfs <- crf_clean |> names() |> unique()
# we remove CRF 29, (and 29_bis below) (AE), 31 (CM), and 34 (Protocol deviation)
visit_crfs <- visit_crfs |> setdiff(str_c("crf", c("27_long", "29", "29_summary", "31", "34", "47_long")))

visits_long <- 
  map(
    visit_crfs,
    ~ crf_clean[[.x]] |> 
      select(pid, any_of(c("visit_code", "study_day"))) |> 
      mutate(crf_plate = .x |> str_remove("crf"))
  ) |>
  bind_rows() |> 
  filter(crf_plate != "29_bis") |> 
  mutate(
    pid = pid |> as.character(),
    crf_plate = crf_plate |> fct_inorder()
    ) 

Overview of visits’s study_day by CRF plates.

visits_long |> 
  left_join(participants, by = join_by(pid)) |> 
  ggplot() +
  aes(x = study_day, y = pid, col = crf_plate) +
  geom_point(size = 0.5, alpha = 0.5) +
  ggh4x::facet_nested(vars(site, randomized), scales = "free_y", space = "free_y") +
  ggtitle("All participants")

Warning: Removed 10110 rows containing missing values or values outside the scale range
(`geom_point()`).

g_randomized <- 
  visits_long |> 
  left_join(participants, by = join_by(pid)) |> 
  filter(randomized) |> 
  ggplot() +
  aes(x = study_day, y = pid, col = crf_plate) +
  geom_point(size = 0.5, alpha = 0.5) +
  facet_grid(site + randomized ~ ., scales = "free_y", space = "free_y") +
  ggtitle("Randomized participants")

g_randomized + scale_x_continuous(limits = c(-100, 150))

Warning: Removed 7991 rows containing missing values or values outside the scale range
(`geom_point()`).

And by visit code.

g_randomized <- 
  visits_long |> 
  left_join(participants, by = join_by(pid)) |> 
  filter(randomized) |> 
  ggplot() +
  aes(x = study_day, y = pid, col = visit_code) +
  geom_point(size = 0.5, alpha = 0.5) +
  facet_grid(site + randomized ~ ., scales = "free_y", space = "free_y") + 
  # scale_x_continuous(limits = c(-100, 150)) +
  ggtitle("Randomized participants")

g_randomized + scale_x_continuous(limits = c(-100, 150))

Warning: Removed 7991 rows containing missing values or values outside the scale range
(`geom_point()`).

Overview of visit_code

g_randomized <- 
  visits_long |> 
  filter(!is.na(visit_code)) |> 
  arrange(pid, visit_code) |> 
  group_by(pid, visit_code) |> 
  mutate(n_distinct_study_days = study_day |> na.omit() |>  n_distinct()) |> 
  ungroup() |> 
  left_join(participants, by = join_by(pid)) |> 
  filter(randomized) |> 
  ggplot() +
  aes(x = study_day, y = pid, col = n_distinct_study_days |> factor()) +
  geom_point(size = 0.5, alpha = 0.5) +
  facet_grid(~ visit_code , scales = "free", space = "free") + 
  scale_color_manual(values = c("steelblue1", colorRampPalette(c("red","black"))(3))) +
  # scale_x_continuous(limits = c(-100, 150)) +
  ggtitle("Randomized participants") +
  theme(strip.text.x = element_text(angle = 90))

g_randomized 

Warning: Removed 7666 rows containing missing values or values outside the scale range
(`geom_point()`).

mismatched_study_days <- 
  visits_long |> 
  filter(!is.na(visit_code)) |> 
  arrange(pid, visit_code) |> 
  group_by(pid, visit_code) |> 
  mutate(n_distinct_study_days = study_day |> na.omit() |>  n_distinct()) |> 
  ungroup() |> 
  filter(n_distinct_study_days > 1) |> 
  filter(!is.na(study_day)) |> 
  group_by(pid, visit_code) |> 
  mutate(
    most_freq_study_day = study_day |> factor() |> fct_infreq() |> levels() |> magrittr::extract(1) |> as.numeric(),
    diff_with_most_freq_study_day = (study_day - most_freq_study_day),
    n_same = sum(study_day == most_freq_study_day),
    n_diff = sum(study_day != most_freq_study_day),
    n = n(),
    f_diff = n_diff / n
    ) |> 
  ungroup()

mismatched_study_days |> 
  filter(visit_code >= 1000) |> 
  gt()

pid	visit_code	study_day	crf_plate	n_distinct_study_days	most_freq_study_day	diff_with_most_freq_study_day	n_same	n_diff	n	f_diff
068200281	2120	83	3	2	83	0	5	3	8	0.375
068200281	2120	83	4	2	83	0	5	3	8	0.375
068200281	2120	91	14	2	83	8	5	3	8	0.375
068200281	2120	83	16	2	83	0	5	3	8	0.375
068200281	2120	83	27	2	83	0	5	3	8	0.375
068200281	2120	91	30	2	83	8	5	3	8	0.375
068200281	2120	83	35	2	83	0	5	3	8	0.375
068200281	2120	91	45	2	83	8	5	3	8	0.375

All mismatches are for screening visits and for just one participant (068200281), it looks like she had some of her 2120 CRF done at one visit and came back for the others.

visits

From the visit_long table, we build the visits table with one row per pid and visit_code and the following columns

• study_day harmonized (= most frequent) (fixed) study_day across CRFs
• visit_type: whether it is a clinic or home visit
• visit_planned: whether the visit was planned or additional
• visit_attended: whether the visit was attended or not. For home visits, this notes whether we have any CRF data for that visit
• specimen_collection_swab (collected, not collected, unclear) [CRF35]
• specimen_collection_softcup (collected, not collected, unclear) [CRF35]
• specimen_collection_cytobrush (collected, not collected, unclear) [CRF35]

We do not document the home swab collection because it looks like there are more mistakes in the CRF data (CRF47) than in the daily swab manifest.

Merging observed and expected visits

observed_visits <- 
  visits_long |>
  filter(!is.na(visit_code)) |> 
  group_by(pid, visit_code) |> 
  summarize(
    study_day = study_day |> na.omit() |> factor() |> fct_infreq() |> levels() |> magrittr::extract(1) |> as.numeric(),
    n_distinct_study_days = study_day |> na.omit() |> n_distinct(),
    crf_plates = crf_plate |> na.omit() |> unique() |> sort() |> str_c(collapse = ", "),
    .groups = "drop"
  ) |> 
  select(pid, visit_code, everything()) |> 
  mutate(visit_attended = TRUE)

expected_visits <- 
  bind_rows(
    participants |> 
      filter(!randomized) |> 
      select(pid) |> 
      mutate(visit_code = "0000"),
    participants |> 
      filter(randomized) |> 
      select(pid) |> 
      expand_grid(
        visit_code = 
          c(
            0, 
            seq(1000, 1500, by = 100), 1700, 1900, 2120,
            1001:1007, 1101:1107, 1201:1207, 1301:1307, 1401:1407, 1501:1503,
            8999
          ) |> sort() |> str_pad(width = 4, pad = "0")
      ) 
  ) |> 
  mutate(
    expected = !(visit_code %in% c(1501:1503)) # we noticed that a few participants had these visits, but they are not "expected"
  )

visits <- 
  full_join(
    observed_visits,
    expected_visits,
    by = join_by(pid, visit_code)
  ) |> 
  mutate(
    expected = expected |> replace_na(FALSE),
    visit_attended = visit_attended |> replace_na(FALSE)
  )

visits <- 
  visits |> 
  left_join(
    crf_clean$crf41 |>
      mutate(pid = pid |> as.character()) |> 
      select(pid, visit_code) |> 
      mutate(interim_visit = TRUE) ,
    by = join_by(pid, visit_code)
  ) |> 
  mutate(
    visit_planned = 
      case_when(
        !is.na(interim_visit) ~ "Documented interim or unscheduled visit (CRF41)",
        expected ~ "Planned visit",
        !expected & visit_attended ~ "Undocumented visit (CRF 41)",
        !expected & !visit_attended ~ "Potential additional daily visit",
        TRUE ~ "???"
      )
  ) |> 
  select(-interim_visit)

visits <- 
  visits |> 
  mutate(
    visit_type = 
      case_when(
        !expected & !(visit_code %in% 1501:1503) ~ "Unclear",
        visit_code == "8999" ~ "Clinic",
        str_detect(visit_code, "0$") ~ "Clinic",
        TRUE ~ "Home"
      ),
  )

visits |> 
  left_join(participants) |> 
  ggplot() +
  aes(x = visit_code, y = pid, col = visit_planned) +
  geom_point() +
  ggh4x::facet_nested(vars(randomized, site), scales = "free", space = "free") +
  theme(
    axis.text.x = element_text(angle = 90, vjust = 0.5)
  )

Joining with `by = join_by(pid)`

visits |> 
  left_join(participants) |> 
  filter(randomized) |> 
  ggplot() +
  aes(x = visit_code, y = pid, col = visit_attended) +
  geom_point() +
  facet_grid(site + randomized ~ . , scales = "free", space = "free") +
  theme(
    axis.text.x = element_text(angle = 90, vjust = 0.5)
  )

Joining with `by = join_by(pid)`

visits |> 
  left_join(participants) |> 
  filter(randomized) |> 
  ggplot() +
  aes(x = visit_code, y = pid, col = visit_type) +
  geom_point() +
  facet_grid(site + randomized ~ . , scales = "free", space = "free") +
  theme(
    axis.text.x = element_text(angle = 90, vjust = 0.5)
  )

Joining with `by = join_by(pid)`

visits <- visits |> select(-expected)

Specimen collection

Clinic visits (CRF35)

• specimen_collection_swab (number of self-collected swabs) [CRF35]
• specimen_collection_softcup (collected, not collected, unclear) [CRF35]
• specimen_collection_cytobrush (collected, not collected, unclear) [CRF35]

visits <- 
  visits |> 
  left_join(
    crf_clean$crf35 |>
      mutate(pid = pid |> as.character()) |> 
      select(pid, visit_code, self_collected_swabs, starts_with("softcup"), endocervical_cytobrush) |> 
      mutate(
        specimen_collection_swab = self_collected_swabs,
        specimen_collection_softcup = 
          case_when(
            (softcup_time_placed == "Not done") ~ "not collected",
            (softcup == "Checked") & str_detect(softcup_time_placed, "[0-9]*:[0-0]*")  ~ "collected",
            (softcup == "Checked") & is.na(softcup_time_placed) ~ "likely collected (duration unknown)",
            (softcup == "Unchecked") & str_detect(softcup_time_placed, "[0-9]*:[0-0]*") ~ "likely collected",
            (softcup == "Unchecked") & !is.na(softcup_time_placed) ~ "unclear",
            ((softcup == "Unchecked") | (softcup == "Not done")) & is.na(softcup_time_placed) ~ "not collected",
            TRUE ~ "???"
          ),
        specimen_collection_cytobrush = 
          case_when(
            (endocervical_cytobrush == "Checked") ~ "collected",
            (endocervical_cytobrush == "Unchecked") ~ "not collected",
            (endocervical_cytobrush == "Not done") ~ "not collected",
            TRUE ~ "???"
          )
      ) |> 
      select(pid, visit_code, starts_with("specimen")),
    by = join_by(pid, visit_code)
  )

visits |> 
  dplyr::count(specimen_collection_swab > 0, specimen_collection_softcup, specimen_collection_cytobrush) |> 
  gt()

specimen_collection_swab > 0	specimen_collection_softcup	specimen_collection_cytobrush	n
FALSE	not collected	not collected	2
TRUE	collected	collected	365
TRUE	collected	not collected	542
TRUE	likely collected	collected	1
TRUE	likely collected	not collected	4
TRUE	likely collected (duration unknown)	not collected	1
TRUE	not collected	collected	3
TRUE	not collected	not collected	326
NA	???	???	7
NA	collected	collected	1
NA	not collected	collected	1
NA	not collected	not collected	10
NA	NA	NA	3974

crf47_long <- 
  crf_clean$crf47 |>
  select(pid, dfseq, study_day, swabs_brought, abnormal_swabs, contains("_visit_code")) |> # , contains("abnormal_swab")
  rename(crf_visit_code = dfseq) |> 
  pivot_longer(
    cols = -c(pid, crf_visit_code, study_day, swabs_brought, abnormal_swabs), 
    names_to = "home_swab_nb", values_to = "home_swab_visit_code"
    ) |>
  mutate(
    home_swab_nb = home_swab_nb |> parse_number()
  ) 

Dictionary

visits_variable_dictionary <- 
  tibble(
    variable = colnames(visits)
  ) |> 
  mutate(
    description = 
      case_when(
        variable == "pid" ~ "Participant ID",
        variable == "visit_code" ~ "4-digit visit code (character)",
        variable == "study_day" ~ "Relative study day with respect to the enrollment visit (day 0)",
        variable == "n_distinct_study_days" ~ "Number of distinct study day for that visit code (most often a number larger than 1 denotes a re-screening visit)",
        variable == "crf_plates" ~ "CRF plates that have been filled at that visit for that participant.",
        variable == "visit_attended" ~ "Whether the visit was attended by the participant. For home visit, it is whether a CRF was filled for that visit code.",
        variable == "visit_planned" ~ "Whether the visit was planned or not.",
        variable == "visit_type" ~ "Type of the visit: clinic or home (or unclear for some 'unexpected' visit codes)",
        variable == "specimen_collection_swab" ~ "Number of self-collected swabs at that visit (CRF35)",
        variable == "specimen_collection_softcup" ~ "Whether softcup was collected at that visit (CRF35)",
        variable == "specimen_collection_cytobrush" ~ "Whether endocervical cytobrush was collected at that visit (CRF35)",
        
        TRUE ~ "???"
      )
  )

visits_variable_dictionary |> gt()

variable	description
pid	Participant ID
visit_code	4-digit visit code (character)
study_day	Relative study day with respect to the enrollment visit (day 0)
n_distinct_study_days	Number of distinct study day for that visit code (most often a number larger than 1 denotes a re-screening visit)
crf_plates	CRF plates that have been filled at that visit for that participant.
visit_attended	Whether the visit was attended by the participant. For home visit, it is whether a CRF was filled for that visit code.
visit_planned	Whether the visit was planned or not.
visit_type	Type of the visit: clinic or home (or unclear for some 'unexpected' visit codes)
specimen_collection_swab	Number of self-collected swabs at that visit (CRF35)
specimen_collection_softcup	Whether softcup was collected at that visit (CRF35)
specimen_collection_cytobrush	Whether endocervical cytobrush was collected at that visit (CRF35)

s# Population flags (ITT, mITT and PP)

The study population flags (ITT, mITT, PP) are built using the following steps and criteria:

• We define an eligibility flag from CRF7 (we take the last screening visit for participants who came twice);

• We create two variables related to sample collection from CRF35 data (Specimen collection)

  • n_swabs_post_product that counts the total number of swabs after product administration (i.e., from the first follow-up visit, which is visit 1200 for all participants, including LC106-o participants))

  • n_swabs_post_product_prior_week7 that counts the total number of swabs from at clinic visits 1200 to 1500 (incl.).

• We identify replaced participants from CRF44 (Replacement) to exclude participants that have been replaced from the PP;

• We determine the number of missed doses from CRF23 (Product Use) and/or our “consolidated” product exposure table to identify participants who took at least one dose of study product (mITT) or 80% of the doses (PP).

• We identif participants who take a concomitant antibiotics (ciprofloxacin, fosfomycin or metonidazole) betweenn day 7 and day 35 from CRF31 to exclude them from the PP;

• Finally, from these variables, we can define:

  • ITT:

    • all randomized participants (have a treatment code in CRF13)

  • mITT:

    • ITT &

    • met eligibility (CRF7) &

    • n_product_doses > 0 &

    • n_swabs_post_product > 0

  • PP:

    • ITT &

    • not replaced (CRF44) &

    • did not meet replacement criteria (CRF33, 20, 31 and 15) &

    • n_product_doses > 0.8 * max_product_doses &

    • n_swabs_post_product_prior_week7 > 0

We first look at the eligibility from CRF7.

# ELIGIBILITY

# we add information about eligibility (CRF7)
eligibility <- 
  crf_clean$crf7 |> 
  select(pid, dfseq, meet_eligibility) |> 
  arrange(pid, dfseq) |> 
  mutate(pid = pid |> as.character()) |> 
  group_by(pid) |> 
  summarize(
    n = n(),
    meet_eligibility = last(meet_eligibility, order_by = dfseq),
    eligibility_all = str_c(meet_eligibility |> unique(), collapse = ", ")
  )

participants <- 
  participants |>
  left_join(
   eligibility |> select(pid, meet_eligibility) |> mutate(meet_eligibility = (meet_eligibility == "Yes")),
    by = join_by(pid)
  ) |> 
  mutate(meet_eligibility = meet_eligibility |> replace_na(FALSE))

rm(eligibility)


participants |> dplyr::count(meet_eligibility, randomized) |> 
  gt::gt(caption = "All eligible participants were randomized") 

All eligible participants were randomized

meet_eligibility	randomized	n
FALSE	FALSE	436
TRUE	TRUE	96

Then, we look at the swabs collected at in-person visits from CRF35.

# COLLECTED SWABS

# We add information from CRF35 about collected swabs at in-person visits
crf35_sub <- 
  crf_clean$crf35 |>
  select(pid, dfseq, self_collected_swabs) |>
  mutate(pid = pid |> as.character()) |> 
  group_by(pid) |>
  # we count how many swabs were collected after the end of intervention (i.e., from visit 1200, for all intervention arms) 
  mutate(
    n_swabs_post_product = sum(self_collected_swabs[dfseq >= 1200], na.rm = TRUE),
    n_swabs_post_product_prior_week7 = sum(self_collected_swabs[(dfseq >= 1200) & (dfseq <= 1500)], na.rm = TRUE)
    ) |>
  ungroup() |> 
  select(pid, n_swabs_post_product, n_swabs_post_product_prior_week7) |>
  distinct()

participants <- 
  participants |> 
  select(-any_of(c("n_swabs_post_product", "n_swabs_post_product_prior_week7"))) |>
  left_join(crf35_sub, by = "pid")  |> 
  mutate(
    n_swabs_post_product = n_swabs_post_product |> replace_na(0),
    n_swabs_post_product_prior_week7 = n_swabs_post_product_prior_week7 |> replace_na(0)
    )
rm(crf35_sub)


participants |> dplyr::count(randomized, n_swabs_post_product > 0, n_swabs_post_product_prior_week7 > 0) |> gt()

randomized	n_swabs_post_product > 0	n_swabs_post_product_prior_week7 > 0	n
FALSE	FALSE	FALSE	436
TRUE	FALSE	FALSE	4
TRUE	TRUE	FALSE	1
TRUE	TRUE	TRUE	91

participants |> 
  filter(randomized, n_swabs_post_product > 0, n_swabs_post_product_prior_week7 == 0) |> 
  left_join(crf_clean$crf35 |> mutate(pid = pid |> as.character()), by = join_by(pid)) |> 
  gt::gt(caption = "Participants that had swabs collected in the extended follow-up period but not in the follow-up period.")

Participants that had swabs collected in the extended follow-up period but not in the follow-up period.

pid	site	location	randomized	arm	meet_eligibility	n_swabs_post_product	n_swabs_post_product_prior_week7	uid	visit_code	dfseq	vdate_fixed	study_day	Softcup time placed	Softcup time removed	specimen1_specify	Other specimen 2 specify	Softcup	Vaginal swab	Sti testing	Amsel criteria and nugent score	Number of self collected swabs	Pap smear	Cervicovaginal swab for hpv	Endocervical cytobrush	Rectal swab	Urine	Urinalysis	Poc pregnancy	Blood sample	Blood for testing hiv	Blood for testing syphilis	Blood for testing hsv	Complete blood count	Blood for testing blood type	Blood for research tube	Other specimen 1	Other specimen 2	Were home swabs collected?	Number of swabs by participant	Condition of collected home swabs	softcup_time_placed_t	softcup_time_removed_t	softcup_collection_duration
068100050	MGH	US	TRUE	Blinded	TRUE	6	0	068100050_0000	0000	0	FALSE	-6	12:21	12:45	psa	NA	Checked	Checked	Checked	Checked	8	Checked	Checked	Unchecked	Checked	Checked	Unchecked	Checked	Checked	Checked	Checked	Checked	Checked	Checked	Unchecked	Checked	Unchecked	No	NA	Blank	0-01-01 12:21:00	0-01-01 12:45:00	24
068100050	MGH	US	TRUE	Blinded	TRUE	6	0	068100050_1000	1000	1000	FALSE	0	12:21	12:45	psa	NA	Checked	Checked	Unchecked	Checked	6	Unchecked	Unchecked	Checked	Checked	Checked	Checked	Checked	Checked	Unchecked	Unchecked	Unchecked	Unchecked	Unchecked	Checked	Checked	Unchecked	No	NA	Blank	0-01-01 12:21:00	0-01-01 12:45:00	24
068100050	MGH	US	TRUE	Blinded	TRUE	6	0	068100050_1100	1100	1100	FALSE	7	12:27	12:50	psa	NA	Checked	Checked	Unchecked	Checked	8	Unchecked	Unchecked	Checked	Checked	Checked	Checked	Checked	Checked	Unchecked	Unchecked	Unchecked	Unchecked	Unchecked	Checked	Checked	Unchecked	Yes	NA	Blank	0-01-01 12:27:00	0-01-01 12:50:00	23
068100050	MGH	US	TRUE	Blinded	TRUE	6	0	068100050_1700	1700	1700	FALSE	50	13:08	13:29	NA	NA	Checked	Checked	Checked	Checked	6	Unchecked	Checked	Checked	Checked	Checked	Checked	Unchecked	Checked	Checked	Checked	Checked	Unchecked	Unchecked	Checked	Checked	Unchecked	No	NA	Blank	0-01-01 13:08:00	0-01-01 13:29:00	21

We then check if the participants have been replaced (CRF44) or met any of the replacement criteria (CFR33 for bleeding, CRF20/31 for antibiotics), CRF15 for HSIL pap).

# REPLACEMENT
# we check if participants have been replaced

crf44_sub <- 
  crf_clean$crf44 |>
  select(pid, reason_replacement) |> 
  mutate(replaced = TRUE) 

participants <- 
  participants |>
  select(-any_of(c("replaced"))) |>
  left_join(crf44_sub |> select(pid, replaced) |> mutate(pid = pid |> as.character()), by = "pid") |> 
  mutate(replaced = replaced |> replace_na(FALSE)) 

rm(crf44_sub)

# or if they met any of the replacement criteria
# from SAP:
# 3.6.3 Bleeding
# If a participant has 3 days of heavy bleeding (i.e. soaking a pad at least once in a day) during study product dosing, or more than 5 days in a row of heavy bleeding during follow-up, an additional participant will be added to that study arm in the remaining randomization matrix.
# 3.6.4 Antibiotics
# If a participant needs antibiotic treatment for any reason (recurrent BV, urinary tract infection, other) before the week 5 visit, an additional participant will be added to that study arm in the remaining randomization matrix.
# 3.6.5 HSIL pap 
# If the Pap smear obtained at the screening visit is read as HSIL, an additional participant will be added to that study arm in the remaining randomization matrix.


# we use CRF 33 (daily diary) for bleeding

crf33_sub <- 
  crf_clean$crf33 |> 
  select(pid, visit_code, vaginal_bleeding) |> 
  left_join(crf_clean$crf13 |> select(pid, group4), by = join_by(pid)) |> 
  mutate(
    period = 
      case_when(
        (visit_code < 1000) ~ "pre-mtz",
        (group4 == "No") & (visit_code %in% 1000:1099) ~ "mtz",
         (group4 == "Yes") & (visit_code %in% 1001:1200) ~ "product",
        (group4 == "No") & (visit_code %in% 1100:1200) ~ "product",
        (visit_code %in% 1201:1500) ~ "follow-up",
        TRUE ~ NA_character_
      )
  ) |> 
  filter(period %in% c("product", "follow-up")) |> 
  group_by(pid, period) |> 
  summarize(
    n_heavy_bleeding = sum(vaginal_bleeding == "Yes - Heavy", na.rm = TRUE), 
    n_max_consecutive_heavy_bleeding = 
      max(
        rle(vaginal_bleeding == "Yes - Heavy")$lengths[rle(vaginal_bleeding == "Yes - Heavy")$values],
        na.rm = TRUE
      ),
    .groups = "drop"
    ) |> 
  mutate(
    replacement_criteria_bleeding = 
      case_when(
        (period == "product" & n_heavy_bleeding >= 3) ~ TRUE,
        (period == "follow-up" & n_max_consecutive_heavy_bleeding >= 5) ~ TRUE,
        TRUE ~ FALSE
      )
  ) |> 
  group_by(pid) |> 
  summarise(
    replacement_criteria_bleeding = any(replacement_criteria_bleeding, na.rm = TRUE),
    .groups = "drop"
  ) 

Warning: There were 175 warnings in `summarize()`.
The first warning was:
ℹ In argument: `n_max_consecutive_heavy_bleeding = max(...)`.
ℹ In group 1: `pid = "068100004"` `period = "follow-up"`.
Caused by warning in `max()`:
! no non-missing arguments to max; returning -Inf
ℹ Run `dplyr::last_dplyr_warnings()` to see the 174 remaining warnings.

# 3.6.4 Antibiotics
# If a participant needs antibiotic treatment for any reason (recurrent BV, urinary tract infection, other) before the week 5 visit, an additional participant will be added to that study arm in the remaining randomization matrix.

# we use CRF 20 (follow-up questionnaire) for antibiotics
crf20_sub <- 
  crf_clean$crf20 |> 
  select(pid, visit_code, used_during_past_week) |> 
  filter(visit_code > 1000, visit_code <= 1500) |> 
  group_by(pid) |> 
  summarize(
    any_antibiotics = any(str_detect(used_during_past_week, "antibiotic"))
  )

# we use CRF 31 (concomitant medications) for antibiotics, we filter participants who take ciprofloxacin, fosfomycin or metronidazole before study_day 35

crf31_sub <- 
  crf_clean$crf31 |> 
  select(pid, med_start_relative_date, medication) |> 
  left_join(visits |> filter(visit_code == "1500") |> select(pid, visit_code, study_day), by = "pid") |> 
  filter(str_detect(medication, regex("METRONIDAZOLE|FLAGYL|FOSFOMYCIN|CIPROFLOXACIN|CIPROBAY", ignore_case = TRUE))) |>
  filter(med_start_relative_date < study_day) |> #  med_start_relative_date > 7 
  mutate(
    any_antibiotics_crf31 = TRUE
  ) |> 
    select(pid, any_antibiotics_crf31)

# 3.6.5 HSIL pap 
# If the Pap smear obtained at the screening visit is read as HSIL, an additional participant will be added to that study arm in the remaining randomization matrix

# we use CRF 15 (pap smear and blood) for HSIL pap 
crf15_sub <- 
  crf_clean$crf15 |> 
  select(pid, visit_code, pap_smear_results) |> 
  filter(visit_code <= 1000) |> 
  group_by(pid) |> 
  summarize(
    any_HSIL = any(str_detect(pap_smear_results, "HSIL"))
  )


participants <- 
  participants |>
  select(-any_of(c("replacement_criteria_bleeding"))) |>
  left_join(crf33_sub, by = "pid") |> 
  mutate(replacement_criteria_bleeding = replacement_criteria_bleeding |> replace_na(FALSE)) |> 
  select(-any_of(c("any_antibiotics"))) |>
  left_join(crf20_sub, by = "pid") |> 
  mutate(any_antibiotics = any_antibiotics |> replace_na(FALSE)) |> 
  left_join(crf31_sub, by = "pid") |>
  mutate(any_antibiotics_crf31 = any_antibiotics_crf31 |> replace_na(FALSE)) |>
  select(-any_of(c("any_HSIL"))) |>
  left_join(crf15_sub, by = "pid") |>
  mutate(any_HSIL = any_HSIL |> replace_na(FALSE)) |> 
  mutate(meets_replacement_criteria = replacement_criteria_bleeding | any_antibiotics | any_antibiotics_crf31 | any_HSIL) 

participants |> 
  dplyr::count(randomized, replaced, meets_replacement_criteria) |> 
  gt(caption = "Replacement criteria")

Replacement criteria

randomized	replaced	meets_replacement_criteria	n
FALSE	FALSE	FALSE	433
FALSE	FALSE	TRUE	3
TRUE	FALSE	FALSE	86
TRUE	FALSE	TRUE	8
TRUE	TRUE	FALSE	2

We finally look at the product use from CRF23 (Product Use) and/or our “consolidated” product exposure table to identify participants who took at least one dose of study product (mITT) or 80% of the doses (PP).

# PRODUCT USE
# we add information about product use

# two ways: 1 = CRF23 aggregation
crf23_sub <- 
  crf_clean$crf23 |>
  select(pid, dfseq, n_missed_days) |> 
  group_by(pid) |> 
  summarize(
    n_missed_days = 
      case_when(
        all(is.na(n_missed_days)) ~ NA_integer_,
        TRUE ~ sum(n_missed_days, na.rm = TRUE)
      )
    ) |> 
  mutate(n_study_product_doses = 7 - n_missed_days)

# 2. exposures table
# we use exposures table to get the number of study product doses
exposures_studyproduct_summary <- 
  exposures |> 
  mutate(pid = pid |> as.character()) |> 
  group_by(pid) |> 
  summarise(
    n_study_product_doses = sum(as.numeric(study_product), na.rm = TRUE),
  ) |> 
  mutate(
    n_missed_days = 7 - n_study_product_doses
  )

full_join(
  crf23_sub,
  exposures_studyproduct_summary,
  by = "pid"
) |> 
  filter(
    is.na(n_study_product_doses.x) | 
       is.na(n_study_product_doses.y) |
    (n_study_product_doses.x != n_study_product_doses.y)
    ) |> 
  left_join(
    participants |> select(pid, randomized, arm),
    by = "pid"
  ) |> 
  gt(
    caption = "Disagreement between CRF23 and exposures table"
  )

Disagreement between CRF23 and exposures table

pid	n_missed_days.x	n_study_product_doses.x	n_study_product_doses.y	n_missed_days.y	randomized	arm
068100053	6	1	3	4	TRUE	Blinded
068200050	1	6	7	0	TRUE	Blinded
068200281	1	6	7	0	TRUE	Blinded
068200350	NA	NA	0	7	TRUE	Blinded
068100016	NA	NA	0	7	TRUE	Blinded
068100045	NA	NA	0	7	TRUE	Blinded
068100050	NA	NA	4	3	TRUE	Blinded
068100056	NA	NA	0	7	TRUE	Blinded

participants <- 
  participants |> 
  select(-any_of(c("n_study_product_doses_crf23", "n_study_product_doses_exposures"))) |>
  left_join(
    crf23_sub |> 
      mutate(n_study_product_doses_crf23 = n_study_product_doses) |> 
      select(pid, n_study_product_doses_crf23),
    by = "pid"
  ) |> 
  left_join(
    exposures_studyproduct_summary |> 
      mutate(n_study_product_doses_exposures = pmin(7, n_study_product_doses)) |> 
      select(pid, n_study_product_doses_exposures),
    by = "pid"
  ) |> 
  mutate(
    n_study_product_doses_crf23 = n_study_product_doses_crf23 |> replace_na(0),
    n_study_product_doses_exposures = n_study_product_doses_exposures |> replace_na(0)
  )

participants |> 
  dplyr::count(
    randomized, 
    arm,
    n_study_product_doses_crf23 > 1, 
    n_study_product_doses_exposures  > 1
  ) |> 
  gt(caption = "Number of participants with more than 1 dose according to CRF23 or exposures table")

Number of participants with more than 1 dose according to CRF23 or exposures table

randomized	arm	n_study_product_doses_crf23 > 1	n_study_product_doses_exposures > 1	n
FALSE	NA	FALSE	FALSE	436
TRUE	LC-106-o	FALSE	FALSE	1
TRUE	LC-106-o	TRUE	TRUE	15
TRUE	Blinded	FALSE	FALSE	4
TRUE	Blinded	FALSE	TRUE	2
TRUE	Blinded	TRUE	TRUE	74

participants |> 
  dplyr::count(
    randomized, 
    arm,
    n_study_product_doses_crf23 > 5, 
    n_study_product_doses_exposures > 5
  ) |> 
  gt(caption = "Number of participants with more than 5 doses according to CRF23 or exposures table")

Number of participants with more than 5 doses according to CRF23 or exposures table

randomized	arm	n_study_product_doses_crf23 > 5	n_study_product_doses_exposures > 5	n
FALSE	NA	FALSE	FALSE	436
TRUE	LC-106-o	FALSE	FALSE	2
TRUE	LC-106-o	TRUE	TRUE	14
TRUE	Blinded	FALSE	FALSE	6
TRUE	Blinded	TRUE	TRUE	74

We create the population flags.

# create the flag 
participants <- 
  participants |> 
  mutate(
    ITT = randomized,
    mITT = ITT & meet_eligibility & (n_study_product_doses_crf23 > 0) & (n_swabs_post_product > 0),
    PP = ITT & !replaced & !meets_replacement_criteria & (n_study_product_doses_crf23 > 0.8 * 7) & (n_swabs_post_product_prior_week7 > 0)
  )

participants |> 
  dplyr::count(randomized, ITT, mITT, PP) |> 
  gt()

randomized	ITT	mITT	PP	n
FALSE	FALSE	FALSE	FALSE	436
TRUE	TRUE	FALSE	FALSE	6
TRUE	TRUE	TRUE	FALSE	10
TRUE	TRUE	TRUE	TRUE	80

participants <- 
  participants |> 
  select(pid, site, location, randomized, arm, ITT, mITT, PP, everything()) 

Dictionary

participants_variable_dictionary <- 
  tibble(
    variable = colnames(participants)
  ) |> 
  mutate(
    description = 
      case_when(
        variable == "pid" ~ "Participant ID",
        variable == "site" ~ "Study site (MGH or CAP)",
        variable == "location" ~ "Location of the participant (US or SA)",
        variable == "randomized" ~ "Randomized participant (TRUE or FALSE)",
        variable == "arm" ~ "Randomization arm",
        variable == "ITT" ~ "Intention-to-treat population flag (TRUE or FALSE)",
        variable == "mITT" ~ "Modified intention-to-treat population flag (TRUE or FALSE)",
        variable == "PP" ~ "Per-protocol population flag (TRUE or FALSE)",
        variable == "meet_eligibility" ~ "Eligibility flag (TRUE or FALSE): whether participant met eligibility criteria at their last screening visit",
        variable == "n_swabs_post_product" ~ "Number of swabs collected from visit 1200 (incl.)",
        variable == "n_swabs_post_product_prior_week7" ~ "Number of swabs collected from visit 1200 to 1500 (incl.)",
        variable == "replaced" ~ "Replacement flag (TRUE or FALSE): whether participant was replaced",
        variable == "replacement_criteria_bleeding" ~ "Whether participant met replacement criteria related to bleeding.",
        variable == "any_antibiotics" ~ "Whether participant used any antibiotics before visit 1500.",
        variable == "any_HSIL" ~ "Whether participant had HSIL pap at screening visit.",
        variable == "meets_replacement_criteria" ~ "Whether participant meets any of the replacement criteria (bleeding, antibiotics, HSIL pap)",
        variable == "n_study_product_doses_crf23" ~ "Number of doses taken (as reported in CRF23; missing values imputed to 0)",
        variable == "n_study_product_doses_exposures" ~ "Number of doses taken (as reported in exposures table)",
        
        TRUE ~ "???"
      )
  )

participants_variable_dictionary |> gt()

variable	description
pid	Participant ID
site	Study site (MGH or CAP)
location	Location of the participant (US or SA)
randomized	Randomized participant (TRUE or FALSE)
arm	Randomization arm
ITT	Intention-to-treat population flag (TRUE or FALSE)
mITT	Modified intention-to-treat population flag (TRUE or FALSE)
PP	Per-protocol population flag (TRUE or FALSE)
meet_eligibility	Eligibility flag (TRUE or FALSE): whether participant met eligibility criteria at their last screening visit
n_swabs_post_product	Number of swabs collected from visit 1200 (incl.)
n_swabs_post_product_prior_week7	Number of swabs collected from visit 1200 to 1500 (incl.)
replaced	Replacement flag (TRUE or FALSE): whether participant was replaced
replacement_criteria_bleeding	Whether participant met replacement criteria related to bleeding.
any_antibiotics	Whether participant used any antibiotics before visit 1500.
any_antibiotics_crf31	???
any_HSIL	Whether participant had HSIL pap at screening visit.
meets_replacement_criteria	Whether participant meets any of the replacement criteria (bleeding, antibiotics, HSIL pap)
n_study_product_doses_crf23	Number of doses taken (as reported in CRF23; missing values imputed to 0)
n_study_product_doses_exposures	Number of doses taken (as reported in exposures table)

Exports

dir <- get_01_output_dir()

save(participants, file = str_c(dir, "01_participants_", today() |> str_replace_all("-",""), ".Rdata"))
save(participants_variable_dictionary, file = str_c(dir, "01_participants_variable_dictionary_", today() |> str_replace_all("-",""), ".Rdata")) 
save(visits_long, file = str_c(dir, "01_visits_long_", today() |> str_replace_all("-",""), ".Rdata"))
save(visits, file = str_c(dir, "01_visits_", today() |> str_replace_all("-",""),".Rdata"))
save(visits_variable_dictionary, file = str_c(dir, "01_visits_variable_dictionary_", today() |> str_replace_all("-",""), ".RData"))